We evaluated a Biochip (TM)-based immunofluorescence assay for improved diagnosis of dermal-binding pemphigoid diseases by detecting autoantibodies against laminin beta 4, type VII collagen and laminin 332. Results showed high sensitivity, with anti-p200 pemphigoid (laminin beta 4 reactivity) being more frequent than epidermolysis bullosa acquisita, suggesting underdiagnosis in clinical practice. The Biochip mosaic is a valuable tool for the parallel detection of key autoantibodies, potentially enhancing diagnostic accuracy and patient management.

BACKGROUND:Unicentric Castleman disease (UCD), a rare lymphoproliferative disorder, is frequently complicated by paraneoplastic pemphigus (PNP), an autoimmune mucocutaneous syndrome with high mortality. The hyaline-vascular (HV) histological subtype predominates in UCD-PNP, yet the mechanisms driving vascular hyalinization and stromal dysregulation remain poorly defined. OBJECTIVES:To elucidate the cellular and molecular pathogenesis of UCD-PNP through integrated transcriptomic and cellular analyses, focusing on stromal-immune crosstalk and mechanisms underlying extracellular matrix (ECM) dysregulation. METHODS:We performed bulk RNA sequencing (RNAseq) of lymph node samples from 33 patients with pathologically confirmed UCD-PNP and single-cell RNAseq (scRNAseq) in 5 of them. Analytical approaches included differential expression, pathway enrichment, cellular deconvolution, developmental trajectory inference, ligand-receptor interaction analysis and spatial validation. The functional consequences of identified interactions were assessed using bulk RNAseq and proteomic analysis. RESULTS:Bulk RNAseq highlighted ECM dysregulation, with significant upregulation of collagen genes in UCD-PNP. scRNAseq of 58 811 cells revealed expansion of endothelial cells (ECs), pericytes and fibroblasts, alongside diminished follicular dendritic cells (FDCs). Cell-cell communication analysis identified ECs as primary contributors to collagen and laminin overproduction via COL4A1-ITGA1/ITGB1 and LAMB1-ITGA6/ITGB1 signalling, directly linking EC activity to perivascular hyalinization. UCD-PNP also featured marked plasmablast expansion, IgG class-switching and memory CD4+ T cells driving B-cell hyperactivity. In addition, ligand-receptor analysis revealed a pivotal interaction between EC-derived COL4A1 and CD44 on B cells. Mechanistically, COL4A1 overexpression in ECs upregulated genes involved in ECM organization and remodelling. Furthermore, proteomics revealed EC-B-cell crosstalk-derived vascular basement membrane accumulation (perlecan, encoded by HSPG2) and proinflammatory cytokine release (CCL4) in functional co-cultures. CONCLUSIONS:UCD-PNP pathogenesis centres on aberrant EC expansion and dysregulation, driving simultaneous vascular hyalinization via excessive ECM deposition. Pathological EC-B-cell interactions directly link basement membrane accumulation to proinflammatory signalling. Targeting this EC-driven stromal-immune crosstalk presents a novel therapeutic strategy for UCD-PNP.

The treatment of pemphigus vulgaris (PV) often requires long-term systemic corticosteroids. Although new biologicals like rituximab are changing the landscape, traditional immunosuppressants still prevail in many underdeveloped areas. One such medication is methotrexate (MTX), which has been widely used in autoimmune and autoinflammatory diseases, but its role in treating pemphigus remains somewhat unclear and controversial. This study aimed to evaluate the effect and safety profile of using low-dose MTX in PV patients receiving glucocorticoids. PV patients who visited the Department of Dermatology, Peking University First Hospital from January 2010 to December 2021 were retrospectively screened. Based on different treatment regimens, patients were automatically divided into a corticosteroid monotherapy group and a corticosteroid combined with low-dose MTX group (MTX was administered at a dose of no more than15 mg per week, with a minimum duration of 8 weeks). All patients were followed up for 1 year. A total of 142 patients with PV were eligible for the study (100 in the corticosteroid monotherapy group and 42 in the corticosteroid combined with low-dose MTX group). The Kaplan-Meier curve indicated that the corticosteroid combined with low-dose MTX group achieved a 50% reduction in glucocorticoid use faster, with a P value of 0.0132, especially among patients who initially received more than 60 mg of steroids per day. The inclusion of MTX reduced the occurrence of hyperpilidemia. There was not sufficient evidence to determine if the addition of MTX was associated with more bacterial infection cases for certain. The inclusion of low-dose MTX in the corticosteroid treatment regimen for patients with PV, particularly those receiving high doses, can facilitate the reduction of glucocorticoid dosages and lower the incidence of hyperlipidemia, without increasing the risk of other adverse effects.

Unicentric Castleman disease (UCD) is a rare lymphoproliferative disorder. Paraneoplastic pemphigus (PNP) is a major complication associated with poor UCD prognosis. However, the genomic profiles and prognostic biomarkers of PNP-associated UCD remain unclear. In this study, we performed whole-exome sequencing analysis for 28 matched tumor-normal pairs and 9 tumor-only samples to define the genomic landscape of Chinese patients with PNP-associated UCD. An integrative analysis was performed to identify somatic variants, the mutational signatures, and key pathways in tumors. Besides, we analyzed the relationship among mutated genes, clinical characteristics, and prognosis. Sixty-one somatic mutant genes were identified in >1 patient with PNP-associated UCD. Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%). Signaling molecules and interactions, cellular processes, and signal transduction pathways were enriched. Furthermore, we found that poor overall survival was related to IL6ST variants (P = .02). Finally, we classified PNP-associated UCD into 4 genomic subgroups: IL6ST, PDGFRB, IL6ST-PDGFRB, and an unknown subgroup. In summary, we defined the molecular profile of PNP-associated UCD and identified a potential molecular biomarker for predicting prognosis, which may provide therapeutic targets for treating this severe disorder.

Background: Dupilumab, a novel therapy targeting the T helper (Th) 2-mediated inflammation, is showing clinical benefits in treating bullous pemphigoid (BP). However, limited research investigated the serum biomarkers that reflect the inflammation alterations throughout the disease course. Objectives: To explore the changes of the serum inflammatory biomarkers under dupilumab therapy in BP and establish their correlations with disease severity and clinical outcomes. Methods: This exploratory study evaluated serum samples from 40 patients with BP at baseline, 30 of these patients following 16-week dupilumab therapy, and 20 senior healthy controls. Serum levels of 29 cytokines and chemokines were quantified using the Magnetic Luminex Assay. Results: Two distinct clusters based on serum inflammatory profiles were identified. The first cluster, characterized by elevated levels of inflammatory activation, exhibited worse disease severity and poorer remission outcomes. Following the 16-week dupilumab therapy regimen, a significant suppression of Th2-mediated inflammation in the serum was observed, alongside a relative upregulation of Th1 responses. Patients treated with adjuvant systemic steroids exhibited an enhanced suppression of B cell activating factor compared to those receiving dupilumab alone. Significant correlations were unveiled between Th2 biomarkers and clinical scores, eosinophil counts, and anti-BP180 immunoglobulin G levels. Baseline levels of CCL18, Periostin, interleukin (IL)6, and IL-16 constitute an optimal combination to distinguish between inflammatory clusters. Conclusions: Cluster analysis of serum inflammatory biomarkers provided novel insights into the heterogeneity of the inflammation profiles in BP. Baseline levels of CCL18, Periostin, IL-6, IL-16 emerged as effective predictors for disease severity and therapy response to dupilumab. (c) 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Epidermolysis bullosa acquisita (EBA) rarely develops in childhood. This study retrospectively recruited paediatric patients with EBA (age ≤ 16 years), diagnosed by clinical and histopathological features and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assay (ELISA), and reviews their clinical manifestations, histopathology, immunological features, and responses to various treatments. All 7 included patients presented with inflammatory EBA. Among them, 3 had a bullous pemphigoid-like phenotype. Pathologically, in addition to dermal–epidermal blistering, in all patients, the distribution of neutrophils was superficial perivascular or interstitial, or in the dermal papilla. Mixed neutrophils and eosinophils were detected in 2 of the 3 patients with bullous pemphigoid-like phenotypes. In addition to treatment with glucocorticoids, dapsone was administered in 4 patients, while thalidomide and sulfasalazine were administered in 1 patient. All patients responded to the these therapies. Relapse was mainly due to reduction and cessation of glucocorticoids. In conclusion, EBA in childhood may be unique, and thus distinct from its adult counterpart. Specific treatment and follow-up protocols are required for therapy of this rare autoimmune skin disease in children.

Epidermolysis bullosa (EB) comprises a heterogeneous group of rare hereditary genodermatoses characterized by increased mucocutaneous fragility and blisters induced by mild trauma. EBS is the most common type, exhibiting skin blistering within the basal or suprabasal layer of the epidermis [ [1] Khani P. Ghazi F. Zekri A. Nasri F. Behrangi E. Aghdam A.M. Mirzaei H. Keratins and epidermolysis bullosa simplex. J. Cell. Physiol. 2018; 234: 289-297 Crossref PubMed Scopus (17) Google Scholar ]. Up to now, more than 75 % of EBS cases can be ascribed to heterozygous or homozygous variants in KRT5 (OMIM # 148040) and KRT14 (OMIM # 148066) [ [1] Khani P. Ghazi F. Zekri A. Nasri F. Behrangi E. Aghdam A.M. Mirzaei H. Keratins and epidermolysis bullosa simplex. J. Cell. Physiol. 2018; 234: 289-297 Crossref PubMed Scopus (17) Google Scholar ]. Herein, we present two patients in a family with autosomal-dominant EBS with hyperpigmentation harboring a previously unreported heterozygous large deletion of KRT14.

Importance Dupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study. Objective To assess the efficacy and safety of dupilumab in patients with BP and evaluate factors that potentially affect short-term and long-term outcomes. Design, Setting, and Participants A retrospective cohort study was conducted from January 1, 2021, to July 31, 2022. The median (IQR) follow-up period was 24.6 (11.5-38.4) weeks. This multicenter study was performed in 6 dermatology departments of the National Autoimmune Bullous Diseases Cooperative Group of China. Adult patients with BP that received 300 mg of dupilumab every 2 weeks following an initial dose of 600 mg were included. Patients were eligible if they had a clinical presentation of BP combined with immunological or pathological evidence. Patients with drug-induced BP, with less than 4 weeks of follow-up, and who received dupilumab or any other biologics within 6 months were excluded. Main Outcomes and Measures The primary outcome was the proportion of patients who achieved disease control within 4 weeks. Disease control was defined as the absence of new lesions and pruritus, combined with the healing of existing lesions. Complete remission rates, relapse rates, changes in Bullous Pemphigoid Disease Area Index (BPDAI) scores, itching numerical rating scale (NRS) scores, laboratory results within 64 weeks, and adverse events (AEs) were also assessed. Results Among 146 patients (median [IQR] age, 73 [64-85] years; 86 [58.9%] male patients) included in the study, 127 (87.0%) patients achieved disease control within 4 weeks, with a median (IQR) time of 14 (7-14) days. A total of 52 (35.6%) patients achieved complete remission, and 13 (8.9%) patients relapsed during the observation period. The complete remission rate and cumulative relapse rate at week 64 were 62.5% (5 of 8) and 30.9%, respectively. There was rapid and sustained improvement in clinical indicators and laboratory examination results after dupilumab treatment, including BPDAI scores, itching NRS scores, serum anti-BP180 and anti-BP230 antibodies, total IgE levels, and eosinophil count. Of these 146 patients, 107 (73.3%) did not report any AEs. The most common AEs were infections and eosinophilia. Serum anti-BP180 antibody levels of greater than 50 relative units (RU)/mL (OR, 3.63; 95% CI, 0.97-12.61; P = .045) were associated with 4-week disease control, and male patients were more likely to relapse (HR, 10.97; 95% CI, 1.42-84.92; P = .02). Conclusions and Relevance In this retrospective cohort study, dupilumab treatment was associated with improved clinical symptoms in patients with BP. The safety profile was favorable, although concurrent infection and eosinophilia might pose potential concerns. This study suggests that patients with anti-BP180 antibody levels of at least 50 RU/mL and female sex may respond better.

Introduction Atopic dermatitis (AD) exhibits difference in immune polarization between Caucasians and Asian races due to which an evaluation of the efficacy and safety of Pimecrolimus (PIM) in Asian population is called for. The current study addresses the need via a sub-group analysis of the PETITE study (NCT00120523) to evaluate the safety and efficacy of PIM in Chinese infants. Materials and methods Patients with AD (≥3 months–<12 months of age) were randomized in a 1:1 ratio to either PIM 1% cream or topical corticosteroids (TCS). The primary endpoint was safety. The secondary endpoint was efficacy. Results 120 patients were randomized to either PIM 1% or TCS (n = 61 for PIM, n = 59 for TCS). The most often reported adverse events were reported by similar proportions of patients treated with PIM or TCS. There was a progressive increase in overall IGA treatment success in infants treated with PIM (82.9%, p < .05, 95% CI: 70.4, 95.3) after 26 weeks which was comparable to the TCS group (88.5%, p < .05, 95% CI: 79.8, 97.1). Conclusion PIM showed an early and sustained efficacy in the Chinese sub-population with a substantial corticosteroid-sparing effect in patients with AD.

Therapy discontinuation of systemic glucocorticoid treatment for pemphigus remains uncertain at the clinical end point of complete remission. The objective of this study was to identify the factors associated with achieving complete remission off therapy (CROT) and analyze the occurrence of relapse after therapy discontinuation. A retrospective cohort study was conducted at the Department of Dermatology of Peking University First Hospital. A total of 447 patients with pemphigus treated from 2005 to 2020 were identified. Univariate and multivariate analyses were conducted to analyze the associated factors of CROT and to evaluate the outcomes. The mean age was 48 years (+/- 13.4 years), and 54.6% of the patients were women. During a median follow-up of 59 months (43-87.5 months), 160 of 447 (35.8%) patients achieved CROT after a median treatment duration of 51 months (38-66.2 months). Patients with a shorter therapy duration to complete remission on minimal therapy and negative desmoglein antibodies tested in remission were more likely to achieve early CROT. Thirty-five of 160 (21.9%) patients experienced relapse after CROT. Patients who discontinued therapy without guidance experienced significantly faster and higher occurrences of relapse than those withdrawing under guidance (log-rank p = 0.01). Minimal therapy maintenance <= 8 months from complete remission on minimal therapy and positive desmoglein antibodies tested at withdrawal increased the risk of early relapse after CROT.

BACKGROUND:Mendelian disorders of cornification (MeDOC) are a group of heterogeneous genodermatoses with different genetic bases. The pathogenesis of a substantial group of MeDOC remains to be elucidated.OBJECTIVES:To identify a new causative gene and the pathogenesis of a previously undescribed autosomal-dominant cornification disorder.METHODS:Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants. As the variants were located around the signal peptide (SP) cleavage site of a kallikrein-related peptidase, SP cleavage, subcellular localization and extracellular secretion of the variants were evaluated in eukaryotic overexpression systems by Western blotting or immunocytochemistry. Then the trypsin-like and chymotrypsin-like proteolytic activity of the peptidase and degradation of its catalytic substrate were assayed using the patients' stratum corneum (SC) samples. The morphology of the lamellar bodies and corneodesmosomes (CDs) in the patients' SC was ultrastructurally examined. A mouse model harbouring the equivalent variant was constructed and evaluated histologically.RESULTS:We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma. KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC. In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant. Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients' SC samples. Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients' SC, indicating delayed skin desquamation. Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation. Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype.CONCLUSIONS:We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation. Our findings highlight the essential role of KLKs in maintaining homeostasis of skin keratinization and desquamation.

目的 评价利妥昔单抗治疗难治性大疱性类天疱疮的长期疗效及安全性.方法回顾性纳入 2008-2020 年北京大学第一医院皮肤科应用利妥昔单抗治疗的 9 例难治性大疱性类天疱疮患者,9 例患者使用利妥昔单抗前均曾系统使用糖皮质激素或(和)免疫抑制剂治疗,治疗无效或对上述治疗方案不耐受或发生治疗禁忌证,遂选择利妥昔单抗治疗(淋巴瘤方案或类风湿关节炎方案),并进行长期随访.结果 8 例患者达到完全控制,完全控制时间为 11.3 周(3～28 周);7 例患者达到完全缓解(包括 1 例完全停药),完全缓解平均时间为 20.1 个月(10～28.5 个月).4 例患者出现肺部感染,1 例为组织胞浆菌肺炎,3例为卡氏肺孢子虫肺炎,3 例治愈,1 例在治疗 1.5 个月后死亡.结论 利妥昔单抗虽然可有效治疗难治性大疱性类天疱疮,达到病情长期缓解,但是由于其感染的风险,更适合应用于系统性糖皮质激素或免疫抑制剂治疗无效的较为年轻、免疫状态较好的重症难治的患者,不推荐用于免疫功能低下的人群.

Objective: To detect gene mutation in patients with hypohidrotic ectodermal dysplasia (HED) by using whole exome sequencing, to analyze the pathogenicity of the mutations, and to provide reference for the genetic diagnosis of HED patients. Methods: Peripheral blood genomic DNA was extracted from each of the HED patients and their family members collected in Peking University School and Hospital of Stomatology from August 2016 to August 2021. Whole exome sequencing and sanger sequencing were performed to detect gene mutations. Functions of the rare variants after the database filtering were analyzed by bioinformatics tools. Results: Three reported mutations of ectodysplasin A (EDA) gene (c.2T>C, c.161A>G, c.467G>A) and a mutation of ectodysplasin A receptor (EDAR) gene (c.871G>A) were detected by whole genome sequencing in four HED patients, and were verified by Sanger sequencing in four HED families. The EDAR gene mutation founded in this research was reported in HED patients for the first time. Bioinformatics tools predicted that the mutations of EDA gene detected in this study were highly species conserved and disease-causing. The combined annotation dependent depletion (CADD) scores of EDA gene mutations c.2T>C, c.161A>G and c.467G>A were 22.5, 26.3 and 25.5 respectively, and the genomic evolutionary rate profiling (GERP) scores were 2.16, 2.26 and 2.18 respectively. The EDAR gene mutation c.871G>A detected in this study was species conserved and possibly disease-causing. The CADD and GERP scores of EDAR gene mutation c.871G>A were 22.0 and 1.93 respectively. Conclusions: Three reported mutations of EDA gene and a previously unreported mutation of EDAR gene were detected in four HED families. Different mutations of EDA gene and EDAR gene could make different influence on the protein function and lead to the occurrence of HED.

OBJECTIVE:Our review aims at comparing the morbidity and mortality-related risks associated with the pre-injury administration of VK-antagonists or DOACs in elderly patients with TBI.MATERIALS AND METHODS:We performed a systematic search of the academic literature across five databases (Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE), following PRISMA guidelines. We conducted a random-effect meta-analysis to compare the influence of pre-injury VK-antagonists or DOACs administration on the overall intensive care unit and hospital stays of patients with TBI. We also evaluated the overall risks associated with VK-antagonists and with DOACs for intracranial hemorrhage progression, surgical intervention, and overall mortality in patients with TBI.RESULTS:From 973 studies, we found 11 eligible with 4,991 patients with traumatic brain injury (mean age, 77.82 ± 6.76 years). Our meta-analysis revealed insignificantly higher odds of surgical intervention (OR=1.72) and mortality (OR=1.07) associated with VK-antagonists administration than with DOACs administration. Similarly, we found that the intensive care unit (Hedge's g, 0.13) and hospital (g, 0.26) stays were insignificantly longer for individuals on VK-antagonists than for those on DOAC. Moreover, we observed insignificantly higher intracranial hemorrhage progression risks (OR=1.22) for individuals receiving DOACs than for those receiving VK-antagonists.CONCLUSIONS:This study provides evidence on the morbidity and mortality-related outcomes associated with the pre-injury administration of VK-antagonists or DOACs in patients with TBI. We found no significant differences between VK-antagonists and DOACs on the overall morbidity (hospital and intensive care unit stays, intracranial hemorrhage, and surgical intervention frequency) and mortality outcomes in elderly patients with TBI.

Objective:To retrospectively analyze the efficacy and safety of dupilumab in the treatment of bullous pemphigoid (BP) .Methods:Clinical data were collected from BP patients who received injections of dupilumab at an initial dose of 600 mg followed by an every-2-week regimen at a dose of 300 mg (the frequency of injections could be increased if necessary) in Department of Dermatology, Peking University First Hospital from October 2020 to October 2021, and their clinical manifestations and changes in laboratory indices were analyzed.Results:A total of 21 BP patients treated with dupilumab were included in this study. Nineteen (90.5%) patients achieved complete or marked disease control after 2-week treatment with dupilumab; 12 patients were followed up for 16 weeks, and all maintained complete disease control at 16 weeks. All patients had a bullous pemphigoid disease area index (BPDAI) score of 122.5 ± 51.1 points at baseline, which decreased to 30.6 ± 27.4 points after 2-week treatment with dupilumab ( t = 8.53, P < 0.001) , and continued to decrease to 12.7 ± 9.1 points after 4-week treatment ( t = 9.73, P < 0.001) . Pruritus was markedly relieved in all the 21 patients within 4-week treatment with dupilumab. Among 10 patients with elevated eosinophil counts at baseline, the eosinophil counts markedly decreased in 9 after treatment. The serum IgE level was elevated in 7 patients at baseline, which markedly decreased in 6 after treatment. Viral conjunctivitis occurred in 1 (4.8%) patient, and no adverse reactions were observed in other patients. Conclusion:Dupilumab is effective in the control of BP and relief of pruritus, with a favorable safety profile.